Search results for: intracranial tuberculosis

Authors: Alexandra Emmanuelle Membangbi, Jacky Njiki Bikoï, Esther Del-florence Moni Ndedi, Marie Joseph Nkodo Mindimi, Donatien Serge Mbaga, Elsa Nguiffo Makue, André Chris Mikangue Mbongue, Martha Mesembe, George Ikomey Mondinde, Eric Walter Perfura-yone, Sara Honorine Riwom Essama

Abstract:

Background: Tuberculosis (TB) is one of the top lethal infectious diseases worldwide. In recent years, interferon-γ (INF-γ) release assays (IGRAs) have been established as routine tests for diagnosing TB infection. However, produced INF-γ assessment failed to distinguish active TB (ATB) from latent TB infection (LTBI), especially in TB epidemic areas. In addition to IFN-γ, interleukin-2 (IL-2), another cytokine secreted by activated T cells, is also involved in immune response against Mycobacterium tuberculosis. The aim of the study was to assess the capacity of IFN-γ and IL2 to evaluate the therapeutic response of patients on anti-tuberculosis treatment. Material and Methods: We conducted a cross-sectional study in the Pneumonology Departments of the Jamot Hospital in Yaoundé between May and August 2021. After signed the informed consent, the sociodemographic data, as well as 5 mL of blood, were collected in the crook of the elbow of each participant. Sixty-one subjects were selected (n= 61) and divided into 4 groups as followed: group 1: resistant tuberculosis (n=13), group 2: active tuberculosis (n=19), group 3 cured tuberculosis (n=16), and group 4: presumed healthy persons (n=13). The cytokines of interest were determined using an indirect Enzyme-linked Immuno-Sorbent Assay (ELISA) according to the manufacturer's recommendations. P-values < 0.05 were interpreted as statistically significant. All statistical calculations were performed using SPSS version 22.0 Results: The results showed that men were more 14/61 infected (31,8%) with a high presence in active and resistant TB groups. The mean age was 41.3±13.1 years with a 95% CI = [38.2-44.7], the age group with the highest infection rate was ranged between 31 and 40 years. The IL-2 and INF-γ means were respectively 327.6±160.6 pg/mL and 26.6±13.0 pg/mL in active tuberculosis patients, 251.1±30.9 pg/mL and 21.4±9.2 pg/mL in patients with resistant tuberculosis, while it was 149.3±93.3 pg/mL and 17.9±9.4 pg/mL in cured patients, 15.1±8.4 pg/mL and 5.3±2.6 pg/mL in participants presumed healthy (p <0.0001). Significant differences in IFN-γ and IL-2 rates were observed between the different groups. Conclusion: Monitoring the serum levels of INF-γ and IL-2 would be useful to evaluate the therapeutic response of anti-tuberculosis patients, particularly in the both cytokines association case, that could improve the accuracy of routine examinations.

Keywords: antibiotic therapy, interferon gamma, interleukin 2, tuberculosis

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Authors: M. Kuzhko, M. Gumeniuk, D. Butov, T. Tlustova, O. Denysov, T. Sprynsian

Abstract:

Background: The aim of the research was to determine the effectiveness of chemotherapy using intravenous antituberculosis drugs compared with their oral administration during the intensive phase of treatment. Methods: 152 tuberculosis patients were randomized into 2 groups: Main (n=65) who received isoniazid, ethambutol and sodium rifamycin intravenous + pyrazinamide per os and control (n=87) who received all the drugs (isoniazid, rifampicin, ethambutol, pyrazinamide) orally. Results: After 2 weeks of treatment symptoms of intoxication disappeared in 59 (90.7±3.59 %) of patients of the main group and 60 (68.9±4.9 %) patients in the control group, p<0.05. The mean duration of symptoms of intoxication in patients main group was 9.6±0.7 days, in control group – 13.7±0.9 days. After completing intensive phase sputum conversion was found in all the patients main group and 71 (81.6±4.1 %) patients control group p < 0.05. The average time of sputum conversion in main group was 1.6±0.1 months and 1.9±0.1 months in control group, p > 0.05. In patients with destructive pulmonary tuberculosis time to sputum conversion was 1.7±0.1 months in main group and 2.2±0.2 months in control group, p < 0.05. The average time of cavities healing in main group was 2.9±0.2 months and 3.9±0.2 months in the control group, p < 0.05. Conclusions: In patients with newly diagnosed destructive pulmonary tuberculosis use of isoniazid, ethambutol and sodium rifamycin intravenous in the intensive phase of chemotherapy resulted in a significant reduction in terms of the disappearance of symptoms of intoxication and sputum conversion.

Keywords: intravenous chemotherapy, tuberculosis, treatment efficiency, tuberculosis drugs

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Authors: Jose Hernandez, Lina Martínez, Gustavo Gonzalez, Carlos Lázaro, Diana Castrillon, Jonathan Cardona, Laura Mejía, Yina Sanchez, Luisa Ochoa, Evert Jimenez

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Objectives: Economic analyses of tuberculosis control interventions are usually focused on the payer’s perspective. To assess the overall economic impact of the disease, out-of-pocket and indirect costs are also required. This research is aimed to estimate overall economic impact under DOTS-strategy (Directly Observed Therapy Short Course). Methods: A cross-sectional survey of 91 adult tuberculosis patients in treatment for at least two months was conducted from the society perspective. A standardized questionnaire was used in three different cities of Colombia: Medellin (poverty is 17.7%), Monteria (poverty is 36.9%) and Quibdó (poverty is 51.2%). Costs were converted to 2013 USD and categorized into two periods: diagnostics phase and treatment. Results: The median cost during diagnostics was 13$ (±SD 9.5). The median monthly patient out-of-pocket costs during treatment were 32$ (±SD 6.8), equivalent to 17% of patient’s median monthly income, estimated in 186$ (±SD 23). Costs recorded in Medellin were 47$ in Monteria was 18$ and in Quibdó was 13$. Conclusion: Patient costs under DOTS strategy are high even when services are provided free of charge. The creation or strengthening of community-based treatment supervisors could greatly impact costs of tuberculosis and lower drop-outs.

Keywords: tuberculosis, costs and cost analysis, health promotion, Colombia

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Authors: Mattia Testuzza

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Public health is a social endeavour, which involves many different actors: from extremely stratified, structured health systems to unofficial networks of people and knowledge. Health and diseases are an intertwined individual and social experiences. Both patients and health workers navigate this public space through relations of trust. Trust in healthcare goes from the personal trust between a patient and her/his doctor to the trust of both the patient and the health worker in the medical knowledge and the healthcare system. Trust it is not a given, but it is continuously negotiated, given and gained. The key to understand these essential relations of trust in health is to recognise them as a social practice, which therefore implies agency and power. In these terms, health is constantly public and made public, as trust emerges as a meaningfully political phenomenon. Trust as a power relation can be observed at play in the implementation of public health policies such as the WHO’s Directly-Observed Theraphy Short-course (DOTS), and with the increasing concern for drug-resistance that tuberculosis pose, looking at the role of trust in the healthcare delivery system and implementation of public health policies becomes significantly relevant. The ethnographic fieldwork was carried out in four months through observation of the daily practices at the National Tuberculosis Center of Nepal, and semi-structured interviews with MultiDrug-Resistant Tuberculosis (MDR-TB) patients at different stages of the treatment, their relatives, MDR-TB specialised nurses, and doctors. Throughout the research, the role which trust plays in tuberculosis treatment emerged as one fundamental ax that cuts through all the different factors intertwined with drug-resistance development, unfolding a tension between the DOTS policy, which undermines trust, and the day-to-day healthcare relations and practices which cannot function without trust. Trust also stands out as a key component of the solutions to unforeseen issues which develop from the overall uncertainty of the context - for example, political instability and extreme poverty - in which tuberculosis treatment is carried out in Nepal.

Keywords: trust, tuberculosis, drug-resistance, politics of health

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Authors: Rachel F. Ajayi, Unathi Sidwaba, Usisipho Feleni, Samantha F. Douman, Ezo Nxusani, Lindsay Wilson, Candice Rassie, Oluwakemi Tovide, Priscilla G.L. Baker, Sibulelo L. Vilakazi, Robert Tshikhudo, Emmanuel I. Iwuoha

Abstract:

Pyrazinamide (PZA) is among the first-line pro-drugs in the tuberculosis (TB) combination chemotherapy used to treat Mycobacterium tuberculosis. Numerous reports have suggested that hepatotoxicity due to pyrazinamide in patients is due to inappropriate dosing. It is therefore necessary to develop sensitive and reliable techniques for determining the PZA metabolic profile of diagnosed patients promptly and at point-of-care. This study reports the determination of PZA based on nanobiosensor systems developed from disuccinimidyl octanedioate modified Cytochrome P450-2E1 (CYP2E1) electrodeposited on gold substrates derivatised with (poly(8-anilino-1-napthalene sulphonic acid) PANSA/PVP-AgNPs nanocomposites. The rapid and sensitive amperometric PZA detection gave a dynamic linear range of 2 µM to 16 µM revealing a limit of detection of 0.044 µM and a sensitivity of 1.38 µA/µM. The Michaelis-Menten parameters; KM, KMapp and IMAX were also calculated and found to be 6.0 µM, 1.41 µM and 1.51 µA respectively indicating a nanobiosensor suitable for use in serum.

Keywords: tuberculosis, cytochrome P450-2E1, disuccinimidyl octanedioate, pyrazinamide

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Authors: Hendra Wibowo, Suprayitno Wardoyo, Dhama Shinta

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Introduction: Pediatric pulmonary tuberculosis (TB) incidence was increasing, with many undetected cases. In complicated TB, treatment should consist of returning pulmonary function, preventing further complications, and eliminating bacteria. Complicated TB management was still controversial, and surgery was one of the treatments that should be evaluated in accordance with its role in the treatment of complicated TB. Method: This study was an evidence-based case report. The database used for the literature search were Cochrane, Medline, Proquest, and ScienceDirect. Keywords for the search were ‘primary pulmonary tuberculosis’, ‘surgery’, ‘lung resection’, and ‘children’. Inclusion criteria were studies in English or Indonesian, with children under 18 years old as subject, and full-text articles available. The assessment was done according to Oxford Centre for evidence-based medicine 2011. Results: Six cohort studies were analyzed. Surgery was indicated for patients with complicated TB that were unresponsive towards treatment. It should be noted that the experiments were done before the standard WHO antituberculosis therapy was applied; thus, the result may be different from the current application. Conclusion: Currently, there was no guideline on pulmonary resection. However, surgery yielded better mortality and morbidity in children with complicated pulmonary TB.

Keywords: pediatric, pulmonary, surgery, therapy, tuberculosis

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Authors: Zain Khan, Steve Ahn, Kathy Monypenny, James Fink

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In Australian public hospitals, there were approximately 34,000 reported inpatient falls between 2015 to 2016. The gold standard for diagnosing intracranial injury is non-contrast enhanced brain computed tomography (CTB). Over a three-month timeframe, a total of one hundred and eighty (180) falls were documented between the hours of 4pm and 8am at a large metro hospital. Only three (3) of these scans demonstrated a positive intra-cranial finding. The rationale for scanning varied. The common indications included a fall with head strike, the presence of blood thinning medication, loss of consciousness, reduced Glasgow Coma Scale (GCS), vomiting and new neurological findings. There are several validated tools to aid in decision-making around ordering CTB scans in the acute setting, but no such accepted tool exists for the inpatient space. With further data collection, spanning a greater length of time and through involving multiple centres, work can be done towards generating such a tool that can be utilized for inpatient falls.

Keywords: computed tomography, falls, inpatient, intracranial hemorrhage

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Authors: G. K. Guseynova, V. V. Krylov, L. T. Khamidova, N. A. Polunina, V. A. Lukyanchikov

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The report presents complex ultrasound diagnostics in patients with symptomatic steno-occlusive lesions of extra- and intracranial branches of brachiocephalic arteries (BCA). The tasks and possibilities of ultrasound diagnostics at different stages of treatment of patients with symptomatic occlusion of internal carotid artery (ICA) are covered in detail; qualitative and quantitative characteristics of blood flow; parameters of the wall and lumen of the main arteries of the head; methods of ultrasound examination of indirect assessment of the functional status are presented. Special attention is paid to the description of indicators that are predictors of the consistency of formed extra-intracranial low-flow shunts, examples of functioning and failed anastomoses are analyzed.

Keywords: CBF, cerebral blood flow; CTA, external carotid artery; ICA, internal carotid artery; MCA, middle cerebral artery; MRA, magnetic resonance angiography; OEF, oxygen extraction fraction; TIA, transient ischaemic attack, ultrasound, low-flow bypass, anastomoses

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Authors: M. Kuzhko, M. Gumeniuk, D. Butov, T. Tlustova, O. Denysov, T. Sprynsian

Abstract:

Abstract: The objective of this work was to study the efficacy and safety of inhaled nebulized chemotherapy in the treatment of patients with newly diagnosed pulmonary tuberculosis in comparison with standard antimycobacterial therapy. Materials and methods: The study involved 68 patients aged between 20 and 70 years with newly diagnosed pulmonary tuberculosis. Patients were allocated to two groups. The first (main, n=21) group of patients received standard chemotherapy and further 0.15 g of isoniazid and rifampicin 0.15 g inhaled through a nebulizer, also they received salmeterol 50 mcg + fluticasone propionate 250 mcg at 2 breaths twice a day for 2 months. The second (control, n=47) group of patients received standard chemotherapy, consisting of orally administered isoniazid (0.3 g), rifampicin (0.6 g), pyrazinamide (2 g), ethambutol (1.2 g) with a dose reduction after the intensive phase of the therapy. The anti-TB drugs were procured through the Ukraine’s centralized national supply system. Results: Intoxication symptoms in the first group reduced following 1.39±0.18 months, whereas in the second group, intoxication symptoms reduced following 2.7±0.1 months, p<.001. Moreover, respiratory symptoms regression in the first group was observed following 1.6±0.2 months, whereas in the second group – following 2.5±0.2 months, p<0.05. Bacillary excretion period evaluated within 1 month was reduced, as it was shown by 66.6±10.5% in the main group compared to 27.6±6.5%, p<0.05, in the control group. In addition, period of cavities healing was reduced to 2.9±0.2 months in the main group compared to 3.7±0.1 months, p<0.05, in the control group. Residual radiological lung damage findings (large residual changes) were observed in 22 (23.8±9.5 %) patients of the main group versus 24 (51.0±7.2 %) patients in the control group, p<0.05. After completion of treatment scar stenosis of the bronchi II-III art. diagnosed in 3 (14.2±7.8%) patients in main group and 17 (68.0±6.8%) - control group, p<0.05. The duration of hospital treatment was 2.4±0.4 months in main group and 4.1±0.4 months in control group, p<0.05. Conclusion: Administration of of inhaled nebulized chemotherapy in patients with newly diagnosed pulmonary tuberculosis resulted in a comparatively quick reduction of disease manifestation.

Keywords: inhaled nebulized chemotherapy, pulmonary tuberculosis, tuberculosis, treatment of tuberculosis

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Authors: Mohhamed El Habib Labdouni

Abstract:

Introduction: Co-infection with VIH and tuberculosis poses one of the major ongoing challenges for global TB and AIDS prevention and control. The objective of this study is to raise the issue of the resurgence of TB, in People living with VIH supported in a referent center in western Algeria. Its epidemiological, clinical, biological and radiological new trends, and to compare the mortality rate between early and delayed ART. Methods: It was a prospective study, during 36 months from the 01st/01/2012 to 31st/12/2014, by identifying and analyzing cases of TB-VIH co-infection. Our population was devised in two groups/ early ART and delayed ART. The primary and secondary endpoints were analyzed with Kaplan-Meier curves and log-rank test the period of follow up, which was fixed at 300 weeks. Results: Sixty cases of co-infection TB -VIH were enrolled in our study: 78.3% had pulmonary tuberculosis associated with extra-pulmonary, 13.3% had only pulmonary tuberculosis and 08.3% presented strictly extra-pulmonary TB. The clinical particularity of this co-infection is the frequency of serious localization such us: pleural 23.3%, peritoneal 31.7%, and meningeal suffusion 13.3%.y-.biologicaly we notice the predominance both of pancytopenia and leucoanemia, hyponatremia in 38,6% and hypokalemia in 19,3%. By analyzing Kaplan-Meier survival curves, we notice that early ART initiation is associated with a significant reduction of all-cause mortality (p = 0,000), and we have identified several prognostic factors such as hypokalemia hyponatremia, leukocytosis thrombopenemia leucothrombopenia (p = 0,005). Conclusion: Our study confirms most of the results reported in the literature. Early ART initiation reduces the rate of all-cause mortality, despite the probability of the occurrence of TB-IRIS.

Keywords: TB-HIV co-infection, early ART, hyponatremia, extrapulmonary tuberculosis

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Authors: N. Naga Subrahmanyeswara Rao, Parag Arvind Deshpande

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Understanding nucleotide synthesis reaction of any organism is beneficial to know the growth of it as in Mycobacterium tuberculosis to design anti TB drug. One of the reactions of de novo pathway which takes place in all organisms was considered. The reaction takes places between phosphoribosyl pyrophosphate and orotate catalyzed by orotate phosphoribosyl transferase and divalent metal ion gives orotdine monophosphate, a nucleotide. All the reaction steps of three experimentally proposed mechanisms for this reaction were considered to develop kinetic rate expression. The model was validated using the data for four organisms. This model could successfully describe the kinetics for the reported data. The developed model can serve as a reliable model to describe the kinetics in new organisms without the need of mechanistic determination. So an organism-independent model was developed.

Keywords: mechanism, nucleotide, organism, tuberculosis

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Authors: Yun Wang, Ruoyu Wang, Tuo Chen, Guangxiu Liu, Guodong Chen, Wei Zhang

Abstract:

Tuberculosis (TB) is a major public health problem in China. China has the world's second largest tuberculosis epidemic (after India). Xinjiang almost has the highest annual attendance rate of TB in China, and the province is also famous because of its severe dust storms. The epidemic timing starts in February and ends in July, and the dust storm mainly distribute throughout the spring and early summer, which strongly indicate a close linkage between causative agent of TB and dust storm events. However, mechanisms responsible for the observed patterns are still not clearly indentified. By comparing the information on cases of TB from Centers for Disease Control of China annual reports with dust storm atmosphere datasets, we constructed the relationship between the large scale annual occurrence of TB in Xinjiang, a Northwest province of China, and dust storm occurrence. Regional atmospheric indexes of dust storm based on surface wind speed show a clear link between population dynamics of the disease and the climate disaster: the onset of epidemics and the dust storm defined by the atmospheric index share the same mean year. This study is the first that provides a clear demonstration of connections that exist between TB epidemics and dust storm events in China. The development of this study will undoubtedly help early warning for tuberculosis epidemic onset in China and help nationwide and international public health institutions and policy makers to better control TB disease in Norwest China.

Keywords: dust storm, tuberculosis, Xinjiang province, epidemic

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Authors: Taleb L., Benarbia M., Boutira F. M., Allam H., Boukerche A.

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Introduction and purpose of the study: Meningiomas are the most common non-glial intracranial tumors in adults, accounting for approximately 30% of all central nervous system tumors. The aim of our study is to determine the epidemiological, clinical, therapeutic, and evolutionary characteristics of a cohort of patients with intracranial meningioma treated with radiotherapy at the Emir Abdelkader Cancer Center in Oran. Material and methods: This is a retrospective study of 44 patients during the period from 2014 to 2020. The overall survival and relapse-free survival curves were calculated using the Kaplan-Meier method. Results and statistical analysis: The median age of the patients was 49 years [21-76 years] with a clear female predominance (sex ratio=2.4). The average diagnostic delay was seven months [2 to 24 months], the circumstances of the discovery of which were dominated by headaches in 54.5% of cases (n=24), visual disturbances in 40.9% (n=18), and motor disorders in 15.9% (n=7). The seat of the tumor was essentially at the level of the base of the skull in 52.3% of patients (n=23), including 29.5% (n=13) at the level of the cavernous sinus, 27.3% (n=12) at the parasagittal level and 20.5% (n=9) at the convexity. The diagnosis was confirmed surgically in 36 patients (81.8%) whose anatomopathological study returned in favor of grades I, II, and III in respectively 40.9%, 29.5%, and 11.4% of the cases. Radiotherapy was indicated postoperatively in 45.5% of patients (n=20), exclusive in 27.3% (n=12) and after tumor recurrence in 27.3% of cases (n=18). The irradiation doses delivered were as follows: 50 Gy (20.5%), 54 Gy (65.9%), and 60 Gy (13.6%). With a median follow-up of 69 months, the probabilities of relapse-free survival and overall survival at three years are 93.2% and 95.4%, respectively, whereas they are 71.2% and 80.7% at five years. Conclusion: Meningiomas are common primary brain tumors. Most often benign but can also progress aggressively. Their treatment is essentially surgical, but radiotherapy retains its place in specific situations, allowing good tumor control and overall survival.

Keywords: diagnosis, meningioma, surgery, radiotherapy, survival

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Authors: A. Nusrath Unissa, Sameer Hassan, Luke Elizabeth Hanna

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Altered drug binding may be an important factor in isoniazid (INH) resistance, rather than major changes in the enzyme’s activity as a catalase or peroxidase (KatG). The identification of structural or functional defects in the mutant KatGs responsible for INH resistance remains as an area to be explored. In this connection, the differences in the binding affinity between wild-type (WT) and mutants of KatG were investigated, through the generation of three mutants of KatG, Ser315Thr [S315T], Ser315Asn [S315N], Ser315Arg [S315R] and a WT [S315]) with the help of software-MODELLER. The mutants were docked with INH using the software-GOLD. The affinity is lower for WT than mutant, suggesting the tight binding of INH with the mutant protein compared to WT type. These models provide the in silico evidence for the binding interaction of KatG with INH and implicate the basis for rationalization of INH resistance in naturally occurring KatG mutant strains of Mycobacterium tuberculosis.

Keywords: Mycobacterium tuberculosis, KatG, INH resistance, mutants, modelling, docking

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Authors: Minwuyelet Maru, Solomon Habtemariam, Endalamaw Gadissa, Abraham Aseffa

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Background: Tuberculosis is a major public health problem in Ethiopia. The burden of TB is aggravated by emergence and expansion of drug resistant tuberculosis and different lineages of Mycobacterium tuberculosis (M. tuberculosis) have been reported in many parts of the country. Describing strains of Mycobacterial isolates and drug susceptibility pattern is necessary. Method: Sputum samples were collected from smear positive pulmonary TB patients age >= 7 years between October 1, 2012 to September 30, 2013 and Mycobacterial strains isolated on Loweensten Jensen (LJ) media. Each strain was characterized by deletion typing and Spoligotyping. Drug sensitivity testing was determined with the indirect proportion method using Middle brook 7H10 media and association to determine possible risk factors to drug resistance was done. Result: A total of 144 smear positive pulmonary tuberculosis patients were enrolled. The age of participants ranged from 7 to 78 with mean age of 29.22 (±10.77) years. In this study 82.2% (n=97) of the isolates were sensitive to the four first line anti-tuberculosis drugs and resistance to any of the four drugs tested was 17.8% (n=21). A high frequency of any resistance was observed in isoniazid, 13.6%, (n=16) followed by streptomycin, 11.8% (n=14). No significant association of isoniazid resistance with HIV, sex and history of previous TB treatment was observed but there was significant association with age, high between 31-35 years of age (p=0.01). Majority, 89.9% (n=128) of participants were new cases and only 11.1% (n=16) had history of previous TB treatment. No MDR-TB from new cases and 2 MDRTB (13.3%) was isolated from re-treatment cases which was significantly associated with previous TB treatment (p<0.01). Thirty two different types of spoligotype patterns were identified and 74.1% were grouped in to 13 clusters. The dominant strains were SIT 25, 18.1% (n=21), SIT 53, 17.2% (n=20) and SIT 149, 8.6% (n=10). Lineage 4 is the predominant lineage followed by lineage 3 and lineage 7 comprising 65.5% (n=76), 28.4% (n=33) and 6% (n=7) respectively. Majority of strains from lineage 3 and 4 were SIT 25 (63.6%) and SIT 53 (26.3%) whereas SIT 343 was the dominant strain from lineage 7 (71.4%). Conclusion: Wide spread of lineage 3 and lineage 4 of the modern lineage and high number of strain cluster indicates high ongoing transmission. The high proportion resistance to any of the first line anti-tuberculosis drugs may be a potential source in the emergence of MDR-TB. Wide spread of SIT 25 and SIT 53 having a tendency of ease transmission and presence of higher resistance of isoniazid in working and mobile age group, 31-35 years of age may increase risk of drug resistant strains transmission.

Keywords: tuberculosis, drug susceptibility, strain diversity, lineage, Ethiopia, spoligotyping

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Authors: R. Reshma srilakshmi, S. Shalini, P. Yogeeswari, D. Sriram

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Lysine aminotransferase is a crucial enzyme for dormancy in M. tuberculosis. It is involved in persistence and antibiotic resistance. In present work, we attempted to develop benzthiazole derivatives as lysine aminotransferase inhibitors. In our attempts, we also unexpectedly arrived at an interesting compound 21 (E)-4-(5-(2-(benzo[d]thiazol-2-yl)-2-cyanovinyl)thiophen-2-yl)benzoic acid which even though has moderate activity against persistent phase of mycobacterium, it has significant potency against active phase. In the entire series compound 22 (E)-4-(5-(2-(benzo[d]thiazol-2-yl)-2-cyanovinyl)thiophen-2-yl)isophthalic acid emerged as potent molecule with LAT IC50 of 2.62 µM. It has a significant log reduction of 2.9 and 2.3 fold against nutrient starved and biofilm forming mycobacteria. It was found to be inactive in MABA assay and M.marinum induced zebra fish model. It is also devoid of cytotoxicity. Compound 22 was also found to possess bactericidal effect which is independent of concentration and time. It was found to be effective in combination with Rifampicin in 3D granuloma model. The results are very encouraging as the hit molecule shows activity against active as well as persistent forms of tuberculosis. The identified hit needs further more pharmacokinetic and dynamic screening for development as new drug candidate.

Keywords: benzothiazole, latent tuberculosis, LAT, nutrient starvation

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Authors: A. G. Barua, Uttam Rajkhowa, Pranjal Moni Nath, Nur Abdul Kadir

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Mycobacterium tuberculosis (MTB) is one of the most closely-related intracellular bacterial pathogens, grouped as the M. tuberculosis complex (MTC). MTB, the primary agent of human tuberculosis (TB), can develop clinical TB in animals as 75 percent of canine mycobacterial infection is caused by close contact with an infected human being. In the present study, molecular detection of TB in dogs in three North-eastern states of India, Assam Mizoram, and Nagaland was carried out. So far, there has been a lack of systematic study in these regions, hampered by slow diagnostic methods and poor infrastructure. In an attempt to rectify this situation, molecular epidemiology was carried out for nine months to detect canine TB in a sample of 340 dogs. Isolation of DNA was done with swabs (throat/nasal), nodules of lungs and fluids from 100 suspected dogs and the molecular study were carried out with the help of conventional and real-time PCR. Post-mortem study was also carried out. Our results showed that the prevalence of clinical TB in dogs from a high-risk setting was 1 percent. However, the prevalence of immunological sensitization to M. tuberculosis antigen in dogs living in contact with sputum smeared positive TB cases was almost 50 percent. The latter setting had the maximum impact in terms of TB transmission. During the study period, a survey with a standard questionnaire was carried out in the TB hospitals to study reverse zoonosis. It was observed that an infected human being was one of the major risk factors for dogs to contract the infection. This observation was drawn by examining the probable airborne transmission from humans to their pets or strays. The present study helped to discover the nuances of TB transmission more clearly and systematically as compared to other sporadic tests to detect MTB in canine.

Keywords: Assam and Nagaland, canine TB, India, molecular detection, tuberculosis

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Authors: Gagan Dhawan

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Mycobacterium tuberculosis was described as ‘captain of death’ with an inherent property of multiple drug resistance majorly caused by the competent mechanism of efflux pumps. In this study, various open source tools combining chemo-informatics with bioinformatics were used for efficient in-silico drug designing. The efflux pump, Rv1218c, belonging to the ABC transporter superfamily, which is predicted to be a tetronasin-transporter in M. tuberculosis was targeted. Recent studies have shown that Rv1218c forms a complex with two more efflux pumps (Rv1219c and Rv1217c) to provide multidrug resistance to the bacterium. The 3D structure of the protein was modeled (as the structure was unavailable in the previously collected databases on this gene). The TMHMM analysis of this protein in TubercuList has shown that this protein is present in the outer membrane of the bacterium. Virtual screening of compounds from various publically available chemical libraries was performed on the M. tuberculosis protein using various open source tools. These ligands were further assessed where various physicochemical properties were evaluated and analyzed. On comparison of different physicochemical properties, toxicity and docking, the ligand 2-(hydroxymethyl)-6-[4, 5, 6-trihydroxy-2-(hydroxymethyl) tetrahydropyran-3-yl] oxy-tetrahydropyran-3, 4, 5-triol was found to be best suited for further studies.

Keywords: drug resistance, efflux pump, molecular docking, virtual screening

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Authors: Danylo Brindak, Viktor Liashko, Olexander Chepurniy

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Despite considerable experience in implementation of the best international approaches and services within response to epidemy of multi-drug resistant tuberculosis, the results of situation analysis indicate the presence of faults in this area. In 2014, Ukraine (for the first time) was included in the world’s five countries with the highest level of drug-resistant tuberculosis. The effectiveness of its treatment constitutes only 35% in the country. In this context, the increase in allocation of funds to control the epidemic of multidrug-resistant tuberculosis does not produce perceptible positive results. During 2001-2016, only the Global Fund to fight AIDS, Tuberculosis, and Malaria allocated to Ukraine more than USD 521,3 million for programs of tuberculosis and HIV/AIDS control. However, current conditions in post-Semashko system create little motivation for rational use of resources or cost control at inpatient TB facilities. There is no motivation to reduce overdue hospitalization and to target resources to priority sectors of modern tuberculosis control, including a model of care focused on the patient. In the presence of a line-item budget at medical institutions, based on the input factors as the ratios of beds and staff, there is a passive disposal of budgetary funds by health care institutions and their employees who have no motivation to improve quality and efficiency of service provision. Outpatient treatment of tuberculosis is being implemented in Ukraine since 2011 and has many risks, namely creation of parallel systems, low consistency through dependence on funding for the project, reduced the role of the family doctor, the fragmentation of financing, etc. In terms of reforming approaches to health system financing, which began in Ukraine in late 2016, NGO Infection Control in Ukraine conducted piloting of a new, motivating method of remuneration of employees in primary health care. The innovative aspect of this funding mechanism is cost according to results of treatment. The existing method of payment on the basis of the standard per inhabitant (per capita ratio) was added with motivating costs according to results of work. The effectiveness of such treatment of TB patients at the outpatient stage is 90%, while in whole on the basis of a current system the effectiveness of treatment of newly diagnosed pulmonary TB with positive swab is around 60% in the country. Even though Ukraine has 5.24 TB beds per 10 000 citizens. Implemented pilot model of ambulatory treatment will be used for the creation of costs system according to results of activities, the integration of TB and primary health and social services and their focus on achieving results, the reduction of inpatient treatment of tuberculosis.

Keywords: health care reform, multi-drug resistant tuberculosis, outpatient treatment efficiency, tuberculosis

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Authors: Shokoufeh Roudashti, Shahin Bahari, Fakhri Haghi, Habib Zeighami, Ghazal Naderi, Paniz Shirmast

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Background: Mycobacterium tuberculosis complex (MTBC) causes tuberculosis (TB) in humans and animals. Mycobacterium MTBC is one of the most important species of zoonotic pathogens that can be transmitted from cattle to humans. The disease can transmit to human by direct contact with the infected animals, drinking unpasteurized milk and consumption of uncooked meat. The presence of these opportunistic, pathogenic bacteria in bovine milk has emerged as a public-health concern, especially among individuals who consume raw milk. Tuberculosis MTBC is the predominant infectious cause of morbidity and morality worldwide, It is estimated that one third of the world population (approx. 1.8 billion persons) is infected with M. tuberculosis and each year there are 8 million new cases worldwide. The aim of this study, to detect Mycobacterium MTBC in raw milk samples using polymerase chain reaction (PCR). Materials and Methods: In the present study, 60 raw milk samples were collected from rural areas in Zanjan, Iran. After extraction of DNAs and using special primers for Is6110 gene as a marker, PCR was applied to detect the presence or non-presence of the related gene. Results: According to the findings of this study, 8 (13.5 %) out of 60 milk samples were positive for Mycobacterium spp (P < 0.1). Conclusions: The Outbreak of genus Mycobacteria spp in milk samples were determined to be relatively high in Zanjan, Iran.

Keywords: Mycobacteria spp, raw milk, PCR, Zanjan

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Authors: Aminu Bashir Mohammad, Agwu Ezera, Abdulrazaq G. Habib, Garba Iliyasu

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Background: Drug resistance tuberculosis (DR-TB) continues to be a challenge in developing countries with poor resources. Routine screening for primary DR-TB before commencing treatment is not done in public hospitals in Nigeria, even with the large body of evidence that shows a high prevalence of primary DR-TB. Data on drug resistance and its genetic determinant among follow up TB patients is lacking in Nigeria. Hence the aim of this study was to determine the prevalence and genetic determinant of drug resistance among follow up TB patients in a tertiary hospital in Nigeria. Methods: This was a cross-sectional laboratory-based study conducted on 384 sputum samples collected from consented follow-up tuberculosis patients. Standard microbiology methods (Zeil-Nielsen staining and microscopy) and PCR (Line Probe Assay)] were used to analyze the samples collected. Person’s Chi-square was used to analyze the data generated. Results: Out of three hundred and eighty-four (384) sputum samples analyzed for mycobacterium tuberculosis (MTB) and DR-TB twenty-five 25 (6.5%) were found to be AFB positive. These samples were subjected to PCR (Line Probe Assay) out of which 18(72%) tested positive for DR-TB. Mutations conferring resistance to rifampicin (rpo B) and isoniazid (katG, and or inhA) were detected in 12/18(66.7%) and 6/18(33.3%), respectively. Transmission dynamic of DR-TB was not significantly (p>0.05) dependent on demographic characteristics. Conclusion: There is a need to strengthened the laboratory capacity for diagnosis of TB and drug resistance testing and make these services available, affordable, and accessible to the patients who need them.

Keywords: drug resistance tuberculosis, genetic determinant, intensive phase, Nigeria

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Authors: Oktira Roka Aji, Maelita R. Moeis, Ihsanawati, Ernawati A. Giri-Rachman

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Globally, tuberculosis (TB) remains a leading cause of death. The emergence of multidrug-resistant strains and extensively drug-resistant strains have become a major public concern. One of the potential candidates for drug target is the cytoplasmic domain of PhoR Histidine Kinase, a part of the Two Component System (TCS) PhoR-PhoP in Mycobacterium tuberculosis (Mtb). TCS PhoR-PhoP relay extracellular signal to control the expression of 114 virulent associated genes in Mtb. The 3D structure of PhoR cytoplasmic domain is needed to screen novel drugs using structure based drug discovery. The PhoR cytoplasmic domain from Mtb H37Rv was overexpressed in E. coli BL21(DE3), then purified using IMAC Ni-NTA Agarose his-tag affinity column and DEAE-ion exchange column chromatography. The molecular weight of the purified protein was estimated to be 37 kDa after SDS-PAGE analysis. This sample was used for pre-crystallization screening by applying sitting drop vapor diffusion method using Natrix (HR2-116) 48 solutions crystal screen kit at 25ºC. Needle-like crystals were observed after the seventh day of incubation in test solution No.47 (0.1 M KCl, 0.01 M MgCl2.6H2O, 0.05 M Tris-Cl pH 8.5, 30% v/v PEG 4000). Further testing is required for confirming the crystal.

Keywords: tuberculosis, two component system, histidine kinase, needle-like crystals

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Authors: Alpana Meena

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Background: Tuberculosis is one of the major causes of death in south-east nations. Anti-TB–induced hepatotoxicity (AIH) is associated with a mortality of 6%–12%. The risk is increased when the drugs are combined. Reintroduction of anti-tuberculosis drugs in patients with AIH has never been studied systematically. The present study was planned to see the clinical profile of patients of AIH and the response to reintroduction of therapy. Methods: The trial was conducted in the Department of Medicine, Maulana Azad Medical College and associated Lok Nayak Hospital, on 32 patients with extra-pulmonary tuberculosis who developed AIH. Patients were randomly allocated into 3 groups. In group 1- Isoniazid (INH) and Rifampicin (RIF) were given at full dosages (weight calculated) from day 1. In group 2- RIF was given at maximum dosage from day 1 and INH at maximum dosage from day 8. In group 3- INH was given at maximum dosage from day 1 and RIF at maximum dosage from day 8. Pyrazinamide was added when above regimens were tolerated. Results: The mean age of presentation was 29.37±13.497 years. The incidence was found to be highest in patients with tubercular meningitis (41%) followed by abdominal, pericardial, disseminated, spinal, and lymph nodes. The mean latent period for development of AIH was 7.84 days ± 6.149 days and the median normalization days for LFT’s was 8.81 ± 4.22 days (3-21). In the study, 21% patients had recurrence of AIH with majority of patients having tolerated the reintroduction of drugs. Pyrazinamide was introduced after establishing isoniazid and rifampicin safety, thus emphasizing the role of gradual reintroduction of ATT to avoid the combined effects of hepatotoxicity. Conclusion: To conclude, the recurrence rate of hepatotoxicity was not statistically significant between the three groups studied (p > 0.05), and thus all 3 hepatotoxic drugs can be reintroduced safely in patients developing AIH.

Keywords: anti-tubercular therapy induced hepatotoxicity, extra-pulmonary tuberculosis, reintroduction regimens, risk factors

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Authors: Haji Ali Haji, Hussein Suleman, Ulrike Rivett

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This paper presents the design, development and evaluation of an application prototype developed to support tuberculosis (TB) patients’ treatment adherence. The system makes use of graphics and voice reminders as opposed to text messaging to encourage patients to follow their medication routine. To evaluate the effect of the prototype applications, participants were given mobile phones on which the reminder system was installed. Thirty-eight people, including TB health workers and patients from Zanzibar, Tanzania, participated in the evaluation exercises. The results indicate that the participants found the mobile graphic-based application is useful to support TB treatment. All participants understood and interpreted the intended meaning of every image correctly. The study findings revealed that the use of a mobile visual-based application may have potential benefit to support TB patients (both literate and illiterate) in their treatment processes.

Keywords: ICT4D, mobile technology, tuberculosis, visual-based reminder

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Authors: Smruti Mahapatra, Dipankar Biswas, Richard Um, Michael Meggyesy, Riccardo Serra, Noah Gorelick, Steven Marra, Amir Manbachi, Mark G. Luciano

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Intracranial pressure (ICP) is profoundly regulated by the effects of cardiac pulsation and the volume of the incoming blood. Furthermore, these effects on ICP are incremented by the presence of a rigid skull that does not allow for changes in total volume during the cardiac cycle. These factors play a pivotal role in cerebrospinal fluid (CSF) dynamics and distribution, with consequences that are not well understood to this date and that may have a deep effect on the Central Nervous System (CNS) functioning. We designed this study with two specific aims: (a) To study how pulsatility influences local CSF flow, and (b) To study how modulating intracranial pressure affects drug distribution throughout the SAS globally. In order to achieve these aims, we built an elaborate in-vitro model of the SAS closely mimicking the dimensions and flow rates of physiological systems. To modulate intracranial pressure, we used an intracranially implanted, cardiac-gated, volume-oscillating balloon (CADENCE device). Commercially available dye was used to visualize changes in CSF flow. We first implemented two control cases, seeing how the tracer behaves in the presence of pulsations from the brain phantom and the balloon individually. After establishing the controls, we tested 2 cases, having the brain and the balloon pulsate together in sync and out of sync. We then analyzed the distribution area using image processing software. The in-sync case produced a significant increase, 5x times, in the tracer distribution area relative to the out-of-sync case. Assuming that the tracer fluid would mimic blood flow movement, a drug introduced in the SAS with such a system in place would enhance drug distribution and increase the bioavailability of therapeutic drugs to a wider spectrum of brain tissue.

Keywords: blood-brain barrier, cardiac-gated, cerebrospinal fluid, drug delivery, neurosurgery

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Authors: Seyyed Mohammad Amin Mousavi Sagharchi, Elham Javanroudi

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Introduction: Tuberculosis (TB) is a known disease with hidden features caused by Mycobacterium tuberculosis (MTB). This disease, which is one of the 10 deadliest in the world, has caused millions of deaths in recent decades. Furthermore, TB is responsible for infecting about 30% population of world. Like any infection, TB can activate the immune system by locating and colonization in the human body, especially in the alveoli. TB is granulomatosis, so MTB can absorb the host’s immune cells and other cells to form granuloma. Method: Different databases (e.g., PubMed) were recruited to prepare this paper and fulfill our goals to search and find effective papers and investigations. Results: Immune response to MTB is related to T cell killers and contains CD1, CD4, and CD8 T lymphocytes. CD1 lymphocytes can recognize glycolipids, which highly exist in the Mycobacterial fatty cell wall. CD4 lymphocytes and macrophages form granuloma, and it is the main line of immune response to Mycobacteria. On the other hand, CD8 cells have cytolytic function for directly killing MTB by secretion of granulysin. Other functions and secretion to the deal are interleukin-12 (IL-12) by induction of expression interferon-γ (INF-γ) for macrophages activation and creating a granuloma, and tumor necrosis factor (TNF) by promoting macrophage phagolysosomal fusion. Conclusion: Immune cells in battle with MTB are macrophages, dendritic cells (DCs), neutrophils, and natural killer (NK) cells. These immune cells can recognize the Mycobacterium by various receptors, including Toll-like receptors (TLRs), Nod-like receptors (NLRs), and C-type lectin receptors (CLRs) located in the cell surface. In human alveoli exist about 50 dendritic macrophages, which have close communication with other immune cells in the circulating system and epithelial cells to deal with Mycobacteria. Against immune cells, MTB handles some factors (e.g., cordfactor, O-Ag, lipoarabinomannan, sulfatides, and adenylate cyclase) and practical functions (e.g., inhibition of macrophages).

Keywords: mycobacterium tuberculosis, immune responses, immunological mechanisms, respiratory tuberculosis

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Authors: Ambrish Tiwari, Sudhasini Panda, Archana Singh, Kalpana Luthra, S. K. Sharma

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Introduction: On the basis of available literature we know that various host factors play a role in outcome of Tuberculosis (TB) infection by modulating innate immunity. One such factor is Inducible Nitric Oxide Synthase enzyme (iNOS) which help in the production of Nitric Oxide (NO), an antimicrobial agent. Expression of iNOS is in control of various host factors in which Vitamin D along with its nuclear receptor Vitamin D receptor (VDR) is one of them. Vitamin D along with its receptor also produces cathelicidin (antimicrobicidal agent). With this background, we attempted to investigate the levels of Vitamin D and NO along with their associated molecules in tuberculosis patients and household contacts as compared to healthy controls and assess the implication of these findings in susceptibility to tuberculosis (TB). Study subjects and methods: 100 active TB patients, 75 household contacts, and 70 healthy controls were taken. VDR and iNOS mRNA levels were studied using real-time PCR. Serum VDR, cathelicidin, iNOS levels were measured using ELISA. Serum Vitamin D levels were measured in serum samples using chemiluminescence based immunoassay. NO was measured using colorimetry based kit. Results: VDR and iNOS mRNA levels were found to be lower in active TB group compared to household contacts and healthy controls (P=0.0001 and 0.005 respectively). The serum levels of Vitamin D were also found to be lower in active TB group as compared to healthy controls (P =0.001). Levels of cathelicidin and NO was higher in patient group as compared to other groups (p=0.01 and 0.5 respectively). However, the expression of VDR and iNOS and levels of vitamin D was significantly (P < 0.05) higher in household contacts compared to both active TB and healthy control groups. Inference: Higher levels of Vitamin D along with VDR and iNOS expression in household contacts as compared to patients suggest that vitamin D might have a protective role against TB which prevents activation of the disease. From our data, we can conclude that decreased vitamin D levels could be implicated in disease progression and we can use cathelicidin and NO as a biomarker for early diagnosis of pulmonary tuberculosis.

Keywords: vitamin D, VDR, iNOS, tuberculosis

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Authors: Annika Skansberg

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Electronic cigarettes (e-cigarettes) use vapor to deliver nicotine, have recently become popular, especially amongst adolescents. Because of this, the FDA has decided to regulate e-cigarettes, and therefore would like to determine the abuse liability of the products compared to traditional nicotine products. This will allow them to determine the impact of regulating them on public health and shape the decisions they make when creating new laws. This study assessed the abuse liability of Aroma E-juice Dark Honey Tobacco compared to nicotine using an animal model. This e-liquid contains minor alkaloids that may increase abuse liability compared to nicotine alone. The abuse liability of nicotine alone and e-juice liquid were compared in rats using intracranial self-stimulation (ICSS) thresholds. E-liquid had less aversive effects at high nicotine doses in the ICSS model, suggesting that the minor alkaloids in the e-liquid allow users to use higher doses without experiencing the negative effects felt when using high doses of nicotine alone. This finding could mean that e-cigarettes have a higher abuse liability than nicotine alone, but more research is needed before this can be concluded. These findings are useful in observing the abuse liability of e-cigarettes and will help inform the FDA while regulating these products.

Keywords: electronic cigarettes, intra-cranial self stimulation, abuse liability, anhedonia

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Authors: Prasanthi Malapati, R. Reshma, Vijay Soni, Perumal Yogeeswari, Dharmarajan Sriram

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In the present study, we attempted to develop Mycobacterium tuberculosis (Mtb) inhibitors by exploring the pharmaceutically underexploited enzyme targets which are majorly involved in cell wall biosynthesis of mycobacteria. For this purpose, glutamate racemase (coded by MurI gene) was selected. This enzyme racemize L-glutamate to D-glutamate required for the construction of peptidoglycan in the bacterial cell wall synthesis process. Furthermore this enzyme is neither expressed nor its product, D-glutamate is normally found in mammals, and hence designing inhibitors against this enzyme will not affect the host system as well act as potential antitubercular drugs. A library of BITS in house compounds were screened against Mtb MurI enzyme. Based on docking score, interactions and synthetic feasibility one hit lead was identified. Further optimization of lead was attempted and its derivatives were synthesized. Forty eight derivatives of 2-phenylbenzo[d]oxazole and 2-phenylbenzo[d]thiazole were synthesized and evaluated for Mtb MurI inhibition study, in vitro activities against Mtb, cytotoxicity against RAW 264.7 cell line. Chemical derivatization of the lead resulted in compounds NR-1213 AND NR-1124 as the potent M. tuberculosis glutamate racemase inhibitors with IC50 of 4-5µM which are remarkable and were found to be non-cytotoxic. Molecular dynamics, dormant models and cardiotoxicity studies of the most active molecules are in process.

Keywords: cell wall biosynthesis, dormancy, glutamate racemase, tuberculosis

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Authors: Muhammad Imran Hussain, Ramisha Ibtisam, Tayyaba Fatima, Huba Khalid, Ayesha Aziz, Khansa, Adan Sitara, Anam Shahzad, Aymen Jabeen

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Vitamin D supports the immune system fight TB by inhibiting Interferon-gamma (IFN-γ) and lowering host inflammation. The purpose of the research was to see if giving the vitamin D supplements to TB patients affected their prognosis. A randomized placebo control study of 200 TB patients was performed among which 106 received 400,000 IU of injectable vitamin D3 and 94 received placebo for 2 doses. Assessment was carried out at the end of every month for 3 months. IFN-γ responses to whole blood stimulation generated by the Mycobacterium tuberculosis sonicate (MTBs) antigen and early secreted and T cell activated 6 kDa (ESAT6) were assessed at 0 and 12 weeks. The statistical analysis used descriptive statistics (mean and standard deviation), Friedman's test and Fisher's test. The vitamin D group gained significantly more weight (+3.90 pounds) and had less persistent lung disease on imaging (1.33 zones vs. 1.84 zones). They also had a 50% decrease in cavity size. Additionally, patients with low baseline serum concentrations of 25-(OH)D had a significant increase in MTB-induced IFN-γ production after taking vitamin D supplements. Vitamin D administration in large amounts can hasten the recovery of TB patients. The findings point is a therapeutically useful activity of Vitamin D's in the management for tuberculosis.

Keywords: tuberculosis, vitamin D, interferon gamma, protein, infection

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